MYOGENIC DISORDERS OF THE GALLBLADDER

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Acute cholecystitis (AC) affects 88% of patients with symptomatic gallbladder (GB) stones over a 18 year period and has a significant morbidity and mortality in elderly patients. in spite of its high prevalence, its pathogenesis has yet to be elucidated. Our preliminary studies suggest the hypothesis that human AC develops in a permissive GB environment characterized by GB stasis and impaired muscle cytoprotection that allows biliary aggressive factors to initiate the inflammatory process. This proposal therefore will study the myogenic abnormalities responsible for creating this GB environment and examine hydrophobic bile salts and reactive oxygen species (ROS) as possible aggressive factors. Specifically, it will investigate: 1) the role of bile stasis induced by lithogenic bile and excessive cholesterol (Ch) incorporation by muscle cells that seems to worsen during the inflammatory process; 2) the mechanisms of cytoprotection utilized by GB muscle cells. It will focus on the role of PGE2 in the upregulation of scavengers of free radicals and whether its receptors and pathways remain functional after exposure to soluble mediators of inflammation. It will examine the mechanisms of receptor protection and resistance to agonist induced desensitization a well as the detrimental influence of excessive membrane Ch on cytoprotective functions mediated by PGE2 receptors. Defective PGE2 receptors could make these cells more susceptible to damage by lower concentrations o aggressive factors; 3) whether hydrophobic bile salts and ROS initiate the inflammatory process and cause the muscle defects demonstrated in human and experimental AC. It will examine whether bile stasis enhances the diffusion of bile salts through the GB wall. It will also investigate the mechanisms whereby they affect muscle cells by examining whether they are mediated by ROS and whether they induce cytoprotective responses in normal and defective muscle cells; and, 4) whether hydrophobic bile salts prevent the deleterious effects of hydrophobic bile salts in vitro and whether they are effective in the prophylactic treatment of experimental AC in GB's with normal and lithogenic bile. These studies will be conducted in dissociated muscle cells from human GB's with gallstones with or without AC and from experimental AC induced by ligation of the common bile duct in animals with normal and lithogenic bile. The results of these studies may provide evidence and a rationale in support for using hydrophobic bile acids in the prophylactic treatment of this complication.